1. Field of the Invention
The subject invention pertains to compounds that are useful as anti-inflammatory agents and to compositions containing such compounds as active ingredients. More particularly, the invention concerns novel uses for biologically active bis-heterocyclic compounds, e.g. bis-indoles, and to pharmaceutical compositions containing these compounds. The novel use of the compounds relates to the anti-inflammatory properties of the disclosed bis-heterocyclic compounds. Specifically exemplified herein are the compounds identified as Soritin B, bis-(1H-indol-3-yl)-acetic acid methyl ester, Soritin C, bis-2,2-(1-methyl-indol-3-yl) acetic acid methyl ester, Soritin D, bis-2,2-(1-methyl-indol-3-yl) acetic acid, and their salts, analogs, and derivatives.
2. Description of the Related Art
The prevention and control of inflammation is of prime importance to man, and much research has been devoted to development of compounds having anti-inflammatory properties. Certain methods and chemical compositions have been developed which aid in inhibiting or controlling inflammation, but additional anti-inflammatory methods and compositions are needed.
Bis-heterocyclic compounds, such as bis-indoles, have been previously described as having antimicrobial, antitumor or antiviral activity. See U.S. Pat. Nos. 5,955,462; 6,090,811; and 6,291,501, which are herein incorporated by reference. Specifically, the bis-indole compounds known as topsentins are disclosed in U.S. Pat. No. 4,866,084 and nortopsentins are disclosed in U.S. Pat. No. 4,970,226, which are herein incorporated by reference. Dragmacidin and its related compounds isolated from the marine sponge of the Dragmacidon sp. are disclosed in U.S. Pat. No. 4,895,844, which is herein incorporated by reference. These patents are herein incorporated by reference. These compounds as well as the homocarbonyl topsentins and hamacanthins have also been described as having inhibitory activity against cellular inflammatory responses. See U.S. Pat. Nos. 5,290,777 and 5,464,835, which are also hereby incorporated by reference. The present invention provides compounds having advantageous potent anti-inflammatory activity.
Other advantages and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.
The present invention provides compounds that are useful as anti-inflammatory agents.
In one example, the compounds useful according to the subject invention have the following formula: 
wherein R1-10 are the same or different selected from xe2x80x94H, xe2x80x94OH, halogen, xe2x80x94COOH, xe2x80x94COOR, C1-C8 alkyl, C1-C8 alkoxyl, mesyl, tosyl, xe2x80x94OCOR, or NZ1Z2 (wherein the Zs can be the same or different);
X1 and X2 are the same or different selected from xe2x80x94H, xe2x80x94R, xe2x80x94COY, C(NZ1)Y;
Y is xe2x80x94H, xe2x80x94OH, NZ1Z2 (wherein the Z1, and Z2 can be the same or different) C1-C8 alkyl, C1-C8 alkoxyl or an amino acid linked through the amine functionality forming an amide bond;
Z1 and Z2 are the same or different and independently selected from xe2x80x94H, xe2x80x94OH, C1-C8 alkyl, C1-C8 alkoxyl or xe2x80x94COR; and
R is C1-C8 alkyl, or aryl.
Preferred embodiment of the subject invention pertain to the bis-indole compounds: Soritin A, bis-(1H-indol-3-yl)-acetic acid, HB-238, (I); bis(3,3xe2x80x2indolyl)methane, HB-236, (II); and 2,2-bis(3,3xe2x80x2indolyl) acetaldehyde, HB-237 (III) as follows: 
Another preferred embodiment of the present invention is Soritin B, bis-(1H-indol-3-yl)-acetic acid methyl ester, which has the following structural formula (IV): 
Yet another preferred embodiment of the present invention is Soritin C, bis-2,2-(1-methyl-indol-3-yl) acetic acid methyl ester, which has the following structural formula (V): 
Yet still another preferred embodiment of the present invention is Soritin D, bis-2,2-(1-methyl-indol-3-yl) acetic acid, which has the following structural formula (VI): 
As described herein, the invention also comprises pharmaceutical compositions, e.g. anti-inflammatory compositions, containing as an active ingredient an effective amount, preferably between about 0.1% to about 45.0%, especially about 1.0% to about 25.0%, by weight based on the total weight of the composition, of one or more compounds according to the formula expressed above and a non-toxic, pharmaceutically acceptable carrier or diluent. In addition, a pharmaceutical composition can comprise at least one of the subject compounds and a second component comprising at least one other active compound. Such other active compounds include but are not limited to, anti-inflammatory compounds for example, steroidal compounds, including hydrocortisone and the like; or non-steroidal anti-inflammatory agents, including acetylsalicylic acid (aspirin), ibuprofen, acetaminophen, indomethacin, and the like. The second active ingredient can include antiviral, antibacterial, anti-fungal or other anti-microbial compounds or anti-tumor compounds as well.
As described herein, the invention further comprises processes for the production of compounds and compositions of the invention and novel methods of use thereof, e.g. methods of inhibition of the inflammatory response in an animal.
In accordance with the invention, methods for inhibiting inflammation comprise administering to an animal in need of such treatment an effective amount of the pharmaceutical composition.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed. The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of this specification, illustrate several embodiments of the invention and together with the description serve to explain the principles of the invention.